rs1554969688

Variant names:

• chr11-45934018-AG-A
• rs1554969688
• NM_001352027.3:c.1995delC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001352027.3(PHF21A):​c.1995delC​(p.Ser666ProfsTer91) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P665P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHF21A NM_001352027.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

PHF21A (HGNC:24156): (PHD finger protein 21A) The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).[supplied by OMIM, Nov 2010]

PHF21A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Potocki-Shaffer syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0249 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-45934018-AG-A is Pathogenic according to our data. Variant chr11-45934018-AG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521629.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352027.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21A	NM_001352027.3	MANE Select	c.1995delC	p.Ser666ProfsTer91	frameshift	Exon 19 of 19	NP_001338956.1	Q96BD5-3
	PHF21A	NM_001441167.1		c.2016delC	p.Ser673ProfsTer91	frameshift	Exon 18 of 18	NP_001428096.1
	PHF21A	NM_001441168.1		c.2016delC	p.Ser673ProfsTer91	frameshift	Exon 19 of 19	NP_001428097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21A	ENST00000676320.1	MANE Select	c.1995delC	p.Ser666ProfsTer91	frameshift	Exon 19 of 19	ENSP00000502222.1	Q96BD5-3
	PHF21A	ENST00000323180.10	TSL:1	c.1854delC	p.Ser619ProfsTer91	frameshift	Exon 18 of 18	ENSP00000323152.6	Q96BD5-2
	PHF21A	ENST00000863274.1		c.2013delC	p.Ser672ProfsTer91	frameshift	Exon 18 of 18	ENSP00000533333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554969688; hg19: chr11-45955569;